This invention relates to a hitherto unknown class of compounds that show strong activity in inducing differentiation and inhibiting undesirable proliferation of certain cells, including skin cells and cancer cells, as well as immunomodulating and antiinflammatory effects, to pharmaceutical preparations containing these compounds, to dosage units of such preparations, and to their use in the treatment and/or prophylaxis of diseases characterized by abnormal cell differentiation and/or cell proliferation.
A number of vitamin D analogues have been described that show some degree of selectivity in favour of the cell differentiation inducing/cell proliferation inhibiting activity in vitro as compared to the effects on calcium metabolism in vivo (as measured in increased serum calcium concentration and/or increased urinary calcium excretion), which adversely limit the dosage that can safely be administered to patients. One of the first of these to appear, calcipotril (INN) or calcipotriene (USAN), has been developed on the basis of this selectivity and is now recognized worldwide as an effective and safe drug for the topical treatment of psoriasis.
A study with another vitamin D analogue, seocalcitol, selected on this basis supports the concept that systemically administered vitamin D analogues may inhibit breast cancer cell proliferation in vivo at sub-toxic doses (Colston, K. W. et al., Biochem. Pharmacol. 44, 2273-2280 (1992)).
Another vitamin D analogue, CB1093 (20-epi-22-ethoxy-23-yne-24a, 26a, 27a, trishomo-1xcex1,25(OH)2D3 vitamin D3) (Calverley M. J. et al. In: Vitamin D, Proceedings of the Ninth Workshop on Vitamin D, Orlando, Fla., Walter de Gruyter, Berlin, 1994, pp 85-86; and disclosed in WO 93/19044) has been shown to possess potent activity in an in vitro assay on inhibiting the invasiveness of human carcinoma cells (Hansen C. M. et al. In: Vitamin D, Proceedings of the Ninth Workshop on Vitamin D, Orlando, Fla., Walter de Gruyter, Berlin, 1994, pp 508-509).
CB1093 has also been demonstrated to have potent inhibitory activity on the proliferation of, and stimulatory activity on the differentiation and apoptosis of, different types of cancer cells, such as, brain glial tumor cells in vitro (Baudet, C. et al., Cancer Lett. 1996, 100, 3); MCF-7 breast cancer cells in vitro and in vivo (Colston, K. W., et al., In: Vitamin D, Proceedings of the Tenth Workship on Vitamin D, Strasbourg, France, 1997, University of California, Riverside, 1997, pp 443-450; Danielsson, C. et al., In: Vitamin D, Proceedings of the Tenth Workshop on Vitamin D, Strasbourg, France, 1997, University of California, Riverside, 1997, pp 485-486; Danielsson, C. et al., J. Cellular Biochem., 1997, 66, 552); NB4 acute promyelocytic leukemia cells in vitro (Elstner, E., et al., J. Clin. Invest., 1997, 99, 349); HL-60 and de novo human acute myeloid leukemia cells in vitro (Pakkala, I. et al., Blood 1995, 86(10, Suppl.), 775a; Pakkala, I. et al., Leukemia Research 1997, 21, 321); and MG-63 human osteosarcoma cells in vitro (Ryhxc3xa4nen, S., et al., J. Cellular Biochem. 1998, 70, 414).
CB 1093 also significantly decreased plasma PTH and phosphate levels in chronically uraemic rats with secondary hyperparathyroidism (Hruby, M. et al., Nephrol. Dial. Transplant. 1996, 11, 1781).
The classical calcemic vitamin D activity of CB1093, as determined by the urinary excretion of calcium in rats, has been determined to 27% of that of 1xcex1,25(OH)2D3 and the calcemic activity of seocalcitol in the same assay has been determined to 50% (Danielsson, C. et al., J. Cellular Biochem., 1997, 66, 552). In an in vivo experiment treating rats with mammary tumours with CB1093 (1 xcexcg/kg body weight for 28 days ) there was a 49% reduction of the initial tumour volume, but there was still a slight increase in the serum calcium concentration (ibid.). This indicates that the therapeutic window may still be rather narrow, and concern about possible induced increases in serum calcium levels cannot yet be excluded.
Another problem using vitamin D analogues in the non-topical treatment of hyperproliferative diseases, such as cancer, is metabolic stability in vivo. This stability has to be above a certain minimum level, for a compound to be used in practical therapy. As shown in table 1, the stability of CB1093 in an in vitro-model of metabolic stability, using rat liver homogenate xe2x80x9cS-9xe2x80x9d (Kissmeyer, A.-M. et al., Biochem. Pharmacol., 1997, 53, 1087) is quite low compared to seocalcitol (Txc2xd 1.3 hr) and 1xcex1,25(OH)2D3 (Txc2xd 2.5 hr).
There is therefore a continuing need for new vitamin D analogues with high anti-cell proliferative and/or cell differentiation inducing activity showing an acceptable combination of prolonged therapeutic activity and minimum toxic effects compared to 1xcex1,25(OH)2D3. The purpose of the present invention is to provide such new compounds, which purpose is achieved with the novel compounsd having the general formula I herein.
The compounds of the invention constitute a novel class of vitamin D analogues represented by the general formula I: 
wherein formula R represents hydrogen, or (C1-C6)alkyl, phenyl, or (C7-C9)aralkyl optionally substituted with one or more of (C1-C3)alkyl, F, or phenyl; n is an integer having the value 0, 1, or 2; and X represents hydroxy or halogen.
Preferred embodiments of the invention.
Preferred compounds of formula I are compounds wherein R represents methyl, ethyl, propyl, isopropyl, benzyl, and ortho methylbenzyl, meta methylbenzyl, and para methylbenzyl. More preferably R represents methyl or ethyl. n is preferably 0 or 1; 1 being more preferred. Preferably X represents OH, F, or Cl. Most preferably X represents F or X most preferably represents OH or Cl.
The compounds of the invention can comprise more than one diastereoisomeric form; that is both R and S configurations at the carbon atoms marked 22, 25 and 26 in formula I. The invention covers all these diastereoisomers in pure form and also mixtures thereof. Preferred isomers are compounds having the configurations 22(S),25(S),26(S) and 22(S),25(S),26(R). In addition, prodrugs of compounds of formula I in which one or more of the hydroxy groups are masked as groups that can be reconverted to hydroxy groups in vivo could also be envisaged.
The compounds I may be obtained in crystalline form either directly by concentration from an organic solvent or by crystallisation or recrystallisation from an organic solvent or mixture of said solvent and a co-solvent which may be organic or inorganic, such as water. The crystals may be isolated in essentially solvent-free form or as a solvate, such as a hydrate. The invention covers all crystalline modifications and forms and also mixtures thereof.
Exemplary compounds of the invention are
1(S),3(R)-Dihydroxy-20(R)-(5-ethyl-1(S),5(S),6(S)-trihydroxy-2-heptyn-1-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (Compound 101),
1(S),3(R)-Dihydroxy-20(R)-(5(S),6(S)-dihydroxy-5-ethyl-1(S)-methoxy-2-heptyn-1-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (Compound 102),
1(S),3(R)-Dihydroxy-20(R)-(5(S),6(S)-dihydroxy-1(S)-ethoxy-5-ethyl-2-heptyn-1-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (Compound 103),
1(S),3(R)-Dihydroxy-20(R)-(5(S),6(S)-dihydroxy-5-ethyl-1(S)-(1-propyloxy)-2-heptyn-1-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (Compound 104),
1(S),3(R)-Dihydroxy-20(R)-(1(S)-benzylyloxy-5(S),6(S)-dihydroxy-5-ethyl-2-heptyn-1-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (Compound 105),
1(S),3(R)-Dihydroxy-20(R)-(5(R),6(S)-dihydroxy-1(S)-ethoxy-5-ethyl-2-heptyn-1-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (Compound 106),
1(S),3(R)-Dihydroxy-20(R)-(5(R),6(R)-dihydroxy-1(S)-ethoxy-5-ethyl-2-heptyn-1-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (Compound 107),
1(S),3(R)-Dihydroxy-20(R)-(5(S),6(R)-dihydroxy-1(S)-ethoxy-5-ethyl-2-heptyn-1-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (Compound 108),
(S),3(R)-Dihydroxy-20(R)-(4-ethyl-1(S),4(S),5(S)-trihydroxy-2-hexyn-1-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (Compound 109),
(S),3(R)-Dihydroxy-20(R)-(4(S),5(S)-dihydroxy-1(S)-ethoxy 4 ethyl 2 hexyn-1-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (Compound 111),
1(S),3(R)-Dihydroxy-20(R)-(4-ethyl-1(S),4(R),5(S)-trihydroxy-2-hexyn-1-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (Compound 114),
1(S),3(R)-Dihydroxy-20(R)-(4(R),5(S)-dihydroxy-1(S)-ethoxy-4-ethyl-2-hexyn-1-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (Compound 116),
1(S),3(R)-Dihydroxy-20(R)-(1(S)-ethoxy-5-ethyl-6(S)-fluoro-5(S)-hydroxy-2-heptyn-1-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (compound 149), and
1(S),3(R)-Dihydroxy-20(R)-(1(S)-ethoxy-5-ethyl-6(R)-fluoro-5(S)-hydroxy-2-heptyn-1-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (compound 150).
1(S),3(R)-Dihydroxy-20(R)-(1(S),5(R/S)-dihydroxy-5-ethyl-6(S)-fluoro-2-heptyn-1-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (compound 157)
1(S),3(R)-Dihydroxy-20(R)-(1(S)-ethoxy 5-ethyl-6(S)-fluoro-2-heptyn-5(R/S)-hydroxy 1-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (compound 158)
1(S),3(R)-Dihydroxy-20(R)-(1(S),5(R/S)-dihydroxy-5-ethyl-6(R)-fluoro-2-heptyn-1-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (compound 159)
1(S),3(R)-Dihydroxy-20(R)-(1(S)-ethoxy 5-ethyl-6(R)-fluoro-2-heptyn-5(R/S)-hydroxy 1-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (compound 160)
As used in the specification the following terms have the meaning indicated:
xe2x80x9cAlkylxe2x80x9d refers to any univalent group derived from an alkane by removal of a hydrogen atom from any carbon atom, and includes the subclasses of normal alkyl (n-alkyl), and primary, secondary and tertiary alkyl groups respectively, and having the number of carbon atoms specified, including for example (C1-C3)alkyl, (C1-C6)alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, and n-hexyl. Alkane refers to an acyclic straight or branched hydrocarbon having the general formula CnH2n+2, and therefore consisting entirely of hydrogen atoms and saturated carbon atoms.
xe2x80x9c(C7-C9)aralkylxe2x80x9d refers to any alkyl group substituted with an aromatic group, such as phenyl, and having the total number of carbon atoms specified, preferred are (C7-C8)aralkyl groups. Examples are benzyl, 2-phenyl-ethyl, ortho methylbenzyl, meta methylbenzyl, and para methylbenzyl.
xe2x80x9cHalogenxe2x80x9d means the same or different of fluoro, chloro, bromo, and iodo.
The present invention provides a hitherto undisclosed series of vitamin D analogues which is characterised by the presence of an additional hydroxy group or halogen atom in the 26 position of the side chain. Compared to the prior art vitamin D analogues, illustrated by CB1093, the present new vitamin D analogues have precisely the properties which are demanded (Table 1): Half or less the calcemic activity (in the rat calciuric model) and much higher metabolic stability (in the S-9 rat liver homogenate model), together with an only slightly reduced antiproliferative activity (in two different cancer assays: The U937 leukemia cell assay (Kissmeyer, A.-M. et al., Biochem. Pharmacol., 1997, 53, 1087) and the MCF-7 mammary cancer cell assay (Danielsson, C. et al., J. Cellular Biochem., 1997, 66, 552)). Moreover the activity of the present Compounds I in the HaCaT assay, a psoriasis model (Kissmeyer, A.-M. et al., Biochem. Pharmacol., 1997, 53, 1087), is slightly higher than that of CB1093. The advantageous properties of the 26-hydroxy or 26-halogen vitamin D analogues of the present invention are entirely unexpected, as it is known that a similar introduction of a 26-hydroxy group in seocalcitol results in compounds with drastically reduced activities in both the U937 and the HaCaT assays. All the four possible 26-hydroxy-seocalcitol analogues have been shown to be natural metabolites of seocalcitol in vitro and in vivo in rats and in vitro in humans (Binderup, E., et al., In: Vitamin D, Proceedings of the Tenth Workshop on Vitamin D, Strasbourg, France, 1997, University of California, Riverside, 1997, pp 89-90; Kissmeyer, A.-M. et al., Biochem. Pharmacol., 1997, 53, 1087).
The following standard abbreviations are used throughout this disclosure:
AcOH=acetic acid
18C6=18-Crown-6
b.p.=boiling point
Bn=benzyl
Bu=n-butyl
Comp=Compound No.
DMAP=4-dimethylaminopyridine
DMF=N,N-dimethylformamide
Et=ethyl
EtOAc=ethyl acetate
Exam=Example No.
eqv=equivalent (molar)
Ether=diethyl ether
G.P.=General Procedure No.
Hal=Cl, Br or I
h=hour
Me=methyl
m.p.=melting point
Ms=methanesulfonate
PG=Protective Group
Ph=phenyl
Pr=n-propyl
Prep=Preparation No.
PPTS=pyridinium p-toluenesulfonate
Py=pyridine
TBAF=tetra-n-butylammonium fluoride
TBS=tert butyldimethylsilyl
Tf=trifluromethanesulfonyl
THF=tetrahydrofuran
THP=tetrahydro-4H-pyran-2-yl
TMS=trimethylsilyl
Tol=toluene
Ts=4-toluenesulfonyl
Compounds of formula I, as illustrated in Table 4, may be prepared by the general method of Scheme 1: 
Notes to Scheme 1:
General: X1xe2x95x90Oxe2x88x92PG2, F, Cl, Br, or I
PG1 and PG2=Hydrogen or Protective Groups: the same or different, or a combined bifunctional group.
Q=H or Me3Si; n=1,2 or 3.
(a) CH3NHxe2x80x94OCH3, HCl; EtMgBr (3 eqv)
(b) i) Q-Cxe2x89xa1Cxe2x80x94(CH2)n-Met; (Met=xe2x88x92Li, xe2x88x92MgHal; xe2x88x92AlBr2, xe2x88x92Br+SmI2);
if it is desired (only for Q=H) that: PG1=TMS and X1xe2x95x90O-PG1=O-TBS and Q=H;
ii) Me3SiCl/Et3N/CH2Cl2/DMAP,
or, if it is desired that: PG1-PG2=xe2x80x94C(CH3)2xe2x80x94, i.e. X1xe2x95x90O-PG2(-PG1-), and Q=H:
ii) TBAF/THF, (xe2x86x92PG1=PG2=Q=H)
iii) CH2xe2x95x90C(CH3)xe2x80x94Oxe2x80x94CH3 or (CH3)2C(OCH3)2/TsOH
or, if it is desired that: PG1-TMS and X1xe2x95x90F:
Compounds 509 or 510 (e.g. prepared as in Scheme 1a) replace compounds 503 and 504 of Scheme 1;
or, if it is desired that: PG1=TMS and X1xe2x95x90F, Cl, Br, or I and Q=H:
ii) TBAF/THF, (xe2x86x92PG1=PG2=Q=H, i.e. X1xe2x95x90OH)
iii) Conversion of X1 (xe2x95x90OH) to X1xe2x95x90F, Cl, Br, or I, for example as shown in Scheme 2;
iv) optional conversion of PG1=H to PG1=H to PG1=TMS, e.g. with Me3SiCl/Et3N/CH2Cl2/DMAP
(c) i) II+BuLi; ii) 1; iii) optional alkylation of 22-OH with RZ/base (Z=Good leaving group, e.g. Hal, Ms, Ts, or Tf)
(d) Triplet sensitized photo-isomerization of the vitamin D triene, 5(6)(E) to 5(6)(Z); ii) optional alkylation of 22-OH with RZ/base
(e) i) Deprotection with HF/CH3CN/EtOAc or TBAF/THF, optionally followed by or preceded by PPTS/EtOH. 
Notes to Scheme 1a:
(a) KF, HCONH2, 70xc2x0 C. (method of Fritz-Langhals, E. et al, Tetr. Lett. 1993, 34, 293)
(b) CH3NHxe2x80x94OCH3, HCl, EtMgBr (3 eqv)
Compounds I can be prepared from the vitamin D-derived aldehyde compound 1, a synthesis of which has been reported (Calverley, M. J., Tetrahedron, 1987, 43, 4609.), for example by the routes outlined in Scheme 1, by reaction with an organometallic derivative of the side chain building blocks of general formula II.
The Compounds II to be used for making the Compounds I where Xxe2x95x90OH can be synthesized as follows:
L(xe2x88x92)Ethyl lactate or D(+)ethyl lactate (or the corresponding methyl ester) is protected by silylation with tert-butyldimethylsilyl chloride to give the corresponding ethyl TBS-lactate (501, 502). This is converted, in a direct procedure with ethyl magnesium bromide, to the corresponding ethylketone, (503, 504), via the intermediary N-methoxy-N-methylamides, by the method of Williams, J. M. et al. (Tetr. Lett., 1995, 36, 5461).
The ketone 503 or 504 is converted to the partially protected side chain synthon of general formula II by reaction with an organometallic reagent of the type Q-Cxe2x89xa1Cxe2x80x94(CH2)n-Met; (Met=xe2x88x92Li, xe2x88x92MgHal; xe2x88x92AlBr2; xe2x88x92Hal+e.g. Smi2; Q=H or Me3Di; n=1, 2 or 3). In the case of Q-Cxe2x89xa1Cxe2x80x94(CH2)n-Hal+e.g. Smi2, a Barbier type reaction between a halide, a ketone, and a metal/metal salt is referred to.
A mixture of two diasteroisomers is usually formed: The R and the S isomer at the carbon atom marked (25) in Scheme 1, that is the carbon atom which ends up being the carbon atom C(25) in the final compound of formula I. If desired, the two diastereoisomers may be separated at this stage, or later during the synthesis of the side chain synthons II, if this is more convenient.
The following steps in the synthesis of the fully protected side chain synthons II are: 1) If Q is trimethylsilyl, Q is converted into hydrogen by deprotection, e.g. by means of a base. 2) The unprotected hydroxy group at the carbon marked (25) is protected, e.g. by silylation with TMS-Cl; such that PG1=TMS (and PG2=TBS).
Alternatively the TBS group (PG2) of compound II may be removed, e.g. by TBAF (if Q=TMS, this is converted to H at the same time). The two hydroxy groups at the carbon atoms marked (25) and (26), respectively, can then be protected in one step, by conversion into a cyclic acetal or ketal, e.g. an acetonide (isopropylidene ketal), e.g. by means of e.g. 2-methoxypropene or 2,2-dimethoxypropane and an acid, such that PG1 and PG2 are connected into one group: xe2x80x94C(CH3)2xe2x80x94. Other methods of protection of 1,2-diols are described in the literature, e.g. in: Greene, T. W. and Wuts, P. G. M., xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, Sec. Ed., John Wiley and Sons, New York 1991, pp 118-142. An advantage of using cyclic acetals or ketals, such as acetonides, as protective groups of compounds II is that they are particularly well suited for establishing the stereochemistry at carbons (25) and (26) by way of Nuclear Overhauser Enhancement (NOE) NMR spectroscopy.
The Compounds II to be used for making the Compounds I where Xxe2x95x90F may be synthesized from ketone 509 or 510, using the method of Scheme 1a and the intermediates of Table 1a:
The compounds II to be used for making the Compounds I where X is Cl, Br, or I are preferably made (and for Xxe2x95x90F may be made) from the corresponding Compounds II where O-PG1 and O-PG2 (=X1) are both OH, for example as shown in Scheme 2: 
Note to Scheme 2
The compounds II where X1xe2x95x90Cl or I can be converted to each other or converted to the corresponding compounds where X1xe2x95x90F or Br by standard methods, e.g. as described in: R. C. Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, N.Y., USA, 1989, pp. 337-339 hereby incorporated by reference.
The reaction of the aldehyde 1 with the organometallic reagents derived from the side chain building blocks II, can be performed by standard methods of nucleophilic addition of organometallic reagents to carbonyl compounds; i.e. by reacting the alkyne intermediate II with a Grignard reagent, such as ethyl magnesium bromide, or an alkyl lithium, such as butyl lithium (General Procedure 7) in a suitable anhydrous solvent, such as ether and/or THF, to generate the metal acetylide, then adding 1, to give III after usual aqueous work-up (which is normally implied in all the reactions of Scheme 1. In general the reaction product III is a mixture of the two possible C-22 epimers, here designated IIIA and IIIB. It is usually preferable to separate the IIIA and IIIB epimers which can conveniently be done by chromatography.
Nonlimiting illustrations of such compounds of formula III are given in Tables 3 and 3a. Compounds IIIA are formed in much higher yields than the corresponding IIIB epimers, typically in the ratio of about 95 to 5. Compounds IIIA, IVA and IA have 22(S) stereochemistry, and the corresponding compounds with the suffix B have 22(R) stereochemistry. Compounds IA are the preferred ones.
The optional alkylation of the 22-hydroxy compounds of general formula III or IV to yield the corresponding compound III or IV where R is (C1-C6)alkyl, phenyl, or (C7-C9)aralkyl can be performed by standard methods well known to the specialist. Illustrative, but non limiting, compounds of this sort are listed in Table 3.
In the alkylation reaction use is preferably made of an alkylating agent RZ, in which Z stands for a good leaving group, such as for example Hal, Ms, Tf; the RZ being allowed to react with the anion of the appropriate compound III or IV (Rxe2x95x90H), derived therefrom by means of a suitable strong base, such as an alkali-metal alkoxide, alkyl alkali-metal or alkali-metal hydride. A suitable crown ether may be added as a phase transfer agent to accelerate the alkylation process. A useful method is described in General Procedure 9.
The photo-isomerization of the vitamin D triene, 5(6)(E), Compounds III of Scheme 1, to 5(6)(Z), Compounds IV of Scheme 1, is performed by means of UV-light in the presence of a triplet sensitizer, e.g. anthracene; useful methods are described in General Procedure 8 and and 8a. Nonlimiting illustrations of such compounds of general formula IV are given in Tables 3 and 3a, along with references to the preparation of each compound.
The triplet sensitized photo-isomerization of the vitamin D triene, 5(6)(E), Compounds III, to 5(6)(Z), Compounds IV, and the (optional) alkylation of the 22-OH-group with RHal/base, to form a 22-Oxe2x80x94R compound where Rxe2x89xa0H, may be performed in arbitrary order, according to what is most convenient in each case.
The final step in the synthesis of Compounds I of the present invention, examples of which are listed in Table 4, is one or more deprotection procedures to remove all protective groups of the compounds of general formula IV of Scheme 1. The deprotection may for example be performed either with TBAF to remove silyl groups, like TMS or TBS groups (General Procedure 4), or with HF which removes both silyl groups and acid sensitive protective groups, such as isopropylidene (ketal) groups (General Procedure 10). Alternatively, if both types of protective groups are to be removed, two different selective procedures may be used in sequence, e.g. as described in WO97/46522 (G.P. 7): The silyl groups are removed with TBAF, followed by the use of PPTS which selectively removes acid-sensitive protective groups; (or in the reverse order).
Exemplified Compounds I of the invention are listed in Table 4, the numbered examples giving reference to illustrative methods of synthesis, together with spectroscopic data for the exemplified compounds.
The Compounds, 110, 112-113, 115 and 117-156 are made in a sequence of synthetic steps which is analogous to the sequence used for the preparations of Compounds, 101-109, 111, 114, 116 and 157-160, Examples 1-12 and 16-19:
Compound 1 and the appropriate side chain building blocks of General Formula II, Hxe2x80x94Cxe2x89xa1Cxe2x80x94(CH2)nxe2x80x94C(C2H5)(OPG1)-CH(X1)CH3, are reacted, according to General Procedure 7 (G.P. 7), to give the corresponding compound of formula III.
If not mentioned in Tables 2 or 2a, the compounds II in question can be prepared by similar methods to those applied for the synthesis of the compounds II listed in Tables 2 or 2a.
The compound of formula III is photoisomerized, according to G.P. 8 or 8a, to give the corresponding compound of formula IV.
Optionally, the compound of formula IV and the appropriate alkylating agent RZ are reacted, according to G.P. 9, to give the corresponding compound of formula IV where Rxe2x89xa0H. The photoisomerization step and alkylation step may be performed in the reverse order, if desired.
As the last step, the compound of formula IV is deprotected, according to either G.P. 4 or G.P. 10 to give the Compound I in question.
The present compounds are intended for use in pharmaceutical compositions which are useful in the local or systemic treatment or prophylaxis of human and veterinary disorders, such as e.g. psoriasis (including pustulosis palmoplantaris, acrodermatitis continua and nail psoriasis) and other disturbances of keratinization, HIV-associated dermatoses, wound healing, various cancer forms, such as leukemia, mammary cancer, brain glial tumours, osteosarcoma, myelofibrosis, melanoma, other skin cancers, and of diseases of, or imbalances in, the immune system, such as host versus graft and graft versus host reaction and transplant rejection, and autoimmune diseases, such as discoid and systemic lupus erythematosus, diabetes mellitus and chronic dermatoses of auto-immune type, e.g. scleroderma and pemphigus vulgaris, and inflammatory diseases, such as asthma and rheumatoid arthritis, as well as a number of other diseases states including hyperparathyroidism, particularly secondary hyperparathyroidism associated with renal failure, cognituve impairment or senile dementia (Alzheimers disease) and other neurodegenerative diseases, hypertension, acne, alopecia, skin atrophy, e.g. steroid induced skin atrophy, skin ageing, including photo-ageing, and to their use for promoting osteogenesis and treating/preventing osteoporosis and osteomalacia.
The present compounds may be used in combination with other pharmaceuticals or treatment modalities. In the treatment of psoriasis the present compounds may be used in combination with other antipsoriatic drugs, e.g steroids, or with other treatments e.g. light- or UV-light-treatment or the combined PUVA-treatment. In the treatment of cancer the present compounds may be used in combination with other anti-cancer drugs or anti-cancer treatments, such as radiation treatment. In the prevention of graft rejection and graft versus host reaction, or in the treatment of auto-immune diseases, the present compounds may advantageously be used in combination with other immunosuppressive/immunoregulating drugs or treatments, e.g. with cyclosporin A.
The amount required of a compound of formula I (hereinafter referred to as the active ingredient) for therapeutic effect will, of course, vary both with the particular compound, the route of administration and the mammal under treatment. The compounds of the invention can be administered by the parenteral, intra-articular, enteral or topical routes. They are well absorbed when given enterally and this is the preferred route of administration in the treatment of systemic disorders. In the treatment of dermatological disorders like psoriasis or eye diseases topical or enteral forms are preferred.
While it is possible for an active ingredient to be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical formulation. Conveniently, the active ingredient comprises from 0.1 ppm to 0.1% by weight of the formulation.
The formulations, both for veterinary and for human medical use, of the present invention thus comprise an active ingredient in association with a pharmaceutically acceptable carrier therefore and optionally other therapeutic ingredient(s). The carrier(s) must be xe2x80x9cacceptablexe2x80x9d in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof.
The formulations include e.g. those in a form suitable for oral, ophthalmic, rectal, parenteral (including subcutaneous, intramuscular and intravenous), transdermal, intra-articular and topical, nasal or buccal administration.
By the term xe2x80x9cdosage unitxe2x80x9d is meant a unitary, i.e. a single dose which is capable of being administered to a patient, and which may be readily handled and packed, remaining as a physically and chemically stable unit dose comprising either the active material as such or a mixture of it with solid or liquid pharmaceutical diluents or carriers.
The formulations may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
Formulations of the present invention suitable for oral administration may be in the form of discrete units as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. The active ingredient may also be administered in the form of a bolus, electuary or paste.
Formulations for rectal administration may be in the form of a suppository incorporating the active ingredient and a carrier, or in the form of an enema.
Formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredient which is preferably isotonic with the blood of the recipient. Transdermal formulations may be in the form of a plaster.
Formulations suitable for intra-articular or ophthalmic administration may be in the form of a sterile aqueous preparation of the active ingredient which may be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems may also be used to present the active ingredient for both intra-articular and ophthalmic administration.
Formulations suitable for topical or ophthalmic administration include liquid or semi-liquid preparations such as liniments, lotions, gels, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops.
Formulations suitable for administration to the nose or buccal cavity include powder, self-propelling and spray formulations, such as aerosols and atomizers.
In addition to the aforementioned ingredients, the formulations of this invention may include one or more additional ingredients, such as diluents, binders, preservatives etc.
The compositions may further contain other therapeutically active compounds usually applied in the treatment of the above mentioned pathological conditions, such as other immunosuppressants in the treatment of immunological diseases, or steroids in the treatment of dermatological diseases.
The present invention further concerns a method for treating patients suffering from one of the above pathological conditions, said method consisting of administering to a patient in need of treatment an effective amount of one or more compounds of formula I, alone or in combination with one or more other therapeutically active compounds usually applied in the treatment of said pathological conditions. The treatment with the present compounds and/or with further therapeutically active compounds may be simultaneous or with intervals.
In the systemic treatment daily doses from 0.001-2 xcexcg per kilogram body weight, preferably from 0.002-0.3 xcexcg/kg of mammal body weight, for example 0.003-0.2 xcexcg/kg of a compound of formula I are administered, typically corresponding to a daily dose for an adult human of from 0.2 to 15 xcexcg. In the topical treatment of dermatological disorders, ointments, creams or lotions containing from 0.1-500 xcexcg/g, and preferably from 0.1-100 xcexcg/g, of a compound of formula I are administered. For topical use in ophthalmology ointments, drops or gels containing from 0.1-500 xcexcg/g, and preferably from 0.1-100 xcexcg/g, of a compound of formula I are administered. The oral compositions are formulated, preferably as tablets, capsules, or drops, containing from 0.05-50 xcexcg, preferably from 0.1-25 xcexcg, of a compound of formula I, per dosage unit.
The invention is further illustrated by the following General Procedures, Preparations and Examples: